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Positron emission tomography is a highly sensitive molecular imaging modality, based on the coincident detection of annihilation photons after positron decay. The most used detector is based on dense, fast, and luminous scintillators read out by light sensors. This review covers the various detector concepts for clinical and preclinical systems.

Background Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. F-18-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with F-18-flurpiridaz is feasible in mice. Methods Rest/stress PET-MPI was performed with F-18-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7-8 months. Regadenoson (0.1 mu g/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial F-18-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. Results Tracer kinetics were best described by a two-tissue compartment model. K-1 ranged from 6.7 to 20.0 mL center dot cm(-3)center dot min(-1), while myocardial volumes of distribution (V-T) were between 34.6 and 83.6 mL center dot cm(-3). Of note, myocardial F-18-flurpiridaz uptake (%ID/g) was significantly correlated with K-1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman's coefficients (r(s)) ranged between 0.478 and 0.681, R-2 values were generally low. In contrast, an excellent correlation of myocardial F-18-flurpiridaz uptake with V-T was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R-2 >= 0.98). Notably, K-1 and V-T were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K-1, V-T, and %ID/g F-18-flurpiridaz were virtually identical, suggesting that %ID/g F-18-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice. Conclusion Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with F-18-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents., Journal of Nuclear Cardiology, 30 (1), ISSN:1071-3581, ISSN:1532-6551

Purpose Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. Method A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18F-flortaucipir PET imaging in Alzheimer’s disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. Conclusion This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.

PURPOSE: Further diagnostic testing may be required after a coronary computed tomography angiography (CTA) showing suspected coronary stenosis. Whether myocardial perfusion imaging (MPI) provides further prognostic information post-CTA remains debated. We evaluated the prognosis for patients completing CTA stratified for post-CTA diagnostic work-up using real-world data.METHODS: We identified all patients in our uptake area with angina symptoms undergoing first-time CTA over a 10-year period. Follow-up time was a median of 3.7 years [1.9-5.8]. The primary endpoint was a composite of myocardial infarction or death. The secondary endpoint was late revascularization.RESULTS: During the study period 53,351 patients underwent CTA. Of these, 24% were referred for further down-stream testing, 3,547 (7%) to MPI and 9,135 (17%) to invasive coronary angiography (ICA). The primary and secondary endpoints occurred in 2,026 (3.8%) and 954 (1.8%) patients. Patient-characteristic-adjusted hazard ratios for the primary and secondary endpoint using patients with a normal CTA as reference were 1.37 (1.21-1.55) and 2.50 (1.93-3.23) for patient treated medically, 1.68 (1.39-2.03) and 6.13 (4.58-8.21) for patients referred to MPI and 1.94 (1.69-2.23) and 9.18 (7.16-11.78) for patients referred for ICA, respectively. Adjusted analysis with stratification for disease severity at CTA showed similar hazard ratios for patients treated medically after CTA and patients referred for MPI and treated medically after the MPI.CONCLUSION: In patients completing coronary CTA, second-line MPI testing seems to identify patients at low risk of future events. MPI seems to have the potential to act as gatekeeper for ICA after coronary CTA.

Background: Amyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer’s disease (AD). The Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and ‘Small and Medium-sized enterprises’ (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population. The AMYPAD studies: In the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method. Results: AMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine. Future steps: The AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

The serotonin 1B (5-HT1B) receptor has lately received considerable interest in relation to psychiatric and neurological diseases, partly due to findings based on quantification using Positron Emission Tomography (PET). Although the brainstem is an important structure in this regard, PET radioligand binding quantification in brainstem areas often shows poor reliability. This study aims to improve PET quantification of 5-HT1B receptor binding in the brainstem. Volumes of interest (VOIs) were selected based on a 3D [3H]AZ10419369 Autoradiography brainstem model, which visualized 5-HT1B receptor distribution in high resolution. Two previously developed VOI delineation methods were tested and compared to a conventional manual method. For a method based on template data, a [11C]AZ10419369 PET template was created by averaging parametric binding potential (BPND) images of 52 healthy subjects. VOIs were generated based on a predefined volume and BPND thresholding and subsequently applied to test-retest [11C]AZ10419369 parametric BPND images of 8 healthy subjects. For a method based on individual subject data, VOIs were generated directly on each individual parametric image. Both methods showed improved reliability compared to a conventional manual VOI. The VOIs created with [11C]AZ10419369 template data can be automatically applied to future PET studies measuring 5-HT1B receptor binding in the brainstem.

The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [18F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting KV1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [18F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells.

Background CD4+ T cells are central inflammatory mediators in the pathogenesis of autoimmune rheumatoid arthritis (RA), as they are one of the dominating cell types in synovial inflammation. Molecular imaging of CD4+ T cells has potential role for early detection and monitoring of RA. Here, we developed a new radiotracer for in vivo immunoPET imaging of murine CD4+ T cells and tested it in the collagen-induced arthritis (CIA) mouse model of human RA. Results The tracer, [64Cu]Cu-NOTA-CD4-F(ab)’2 ([64Cu]Cu-NOTA-CD4), was generated from F(ab)’2 fragments of R-anti-mouse CD4 antibodies conjugated to the 2-S-(isothiocyanatbenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) chelator and radiolabeled with copper-64. Accumulation of the tracer and isotype control was evaluated in the CIA model and mice receiving whole-body irradiation (WBI) (5 Gy). The potential of [64Cu]Cu-NOTA-CD4 for response assessment was evaluated in CIA induced mice treated with dexamethasone (DXM). Imaging data were compared with flow cytometry and immunohistochemistry (IHC) of inflammatory cells including CD4+ T cells. [64Cu]Cu-NOTA-CD4 showed increased accumulation in T cell-rich tissues compared with isotype control (p 64Cu]Cu-NOTA-CD4 was observed in T cell-depleted tissue (p + T cells in CIA mice. Conclusions We developed and evaluated a new radiotracer, [64Cu]Cu-NOTA-CD4, for immunoPET imaging of murine CD4+ T cells. [64Cu]Cu-NOTA-CD4 was successfully synthesized by F(ab)’2 fragments of R-anti-mouse CD4 antibodies conjugated to a chelator and radiolabeled with copper-64. We found that our novel CD4 PET tracer can be used for noninvasive visualization of murine CD4+ T cells.

The importance of machine learning (ML) in the clinical environment increases constantly. Differentiation of pathological from physiological tracer-uptake in positron emission tomography/computed tomography (PET/CT) images is considered time-consuming and attention intensive, hence crucial for diagnosis and treatment planning. This study aimed at comparing and validating supervised ML algorithms to classify pathological uptake in prostate cancer (PC) patients based on prostate-specific membrane antigen (PSMA)-PET/CT. Retrospective analysis of 68Ga-PSMA-PET/CTs of 72 PC patients resulted in a total of 77 radiomics features from 2452 manually delineated hotspots for training and labeled pathological (1629) or physiological (823) as ground truth (GT). As the held-out test dataset, 331 hotspots (path.:128, phys.: 203) were delineated in 15 other patients. Three ML classifiers were trained and ranked to assess classification performance. As a result, a high overall average performance (area under the curve (AUC) of 0.98) was achieved, especially to detect pathological uptake (0.97 mean sensitivity). However, there is still room for improvement to detect physiological uptake (0.82 mean specificity), especially for glands. The ML algorithm applied to manually delineated lesions predicts hotspot labels with high accuracy on unseen data and may be an important tool to assist in clinical diagnosis.

Background The deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer’s disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD. Aim To synthesize a new Aβ tracer [18F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects. Methods [18F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [18F]DRKXH1 were investigated. Small-animal-PET was used for [18F]DRKXH1 and [18F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [18F]DRKXH1. Results The yield of [18F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [18F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [18F]DRKXH1. The concentration of [18F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P 18F]-DRKXH1 is higher than that of [18F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [18F]DRKXH1-labeled Aβ plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake. Conclusions [18F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and the central neurons system. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies have improved life expectancy; however, this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, better assessment of dystrophic heart and brain pathophysiology is needed. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration; however, neuroinflammation’s role is largely unknown in DMD despite being prevalent in other neurodegenerative diseases. Here, we present an inflammatory marker translocator protein (TSPO) positron emission tomography (PET) protocol for in vivo concomitant assessment of immune cell response in hearts and brains of a dystrophin-deficient mouse model [mdx:utrn(+/−)]. Preliminary analysis of whole-body PET imaging using the TSPO radiotracer, [18F]FEPPA in four mdx:utrn(+/−) and six wildtype mice are presented with ex vivo TSPO-immunofluorescence tissue staining. The mdx:utrn(+/−) mice showed significant elevations in heart and brain [18F]FEPPA activity, which correlated with increased ex vivo fluorescence intensity, highlighting the potential of TSPO-PET to simultaneously assess presence of cardiac and neuroinflammation in dystrophic heart and brain, as well as in several organs within a DMD model.

Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides 177Lu and 225Ac. This was improved with the dimer DOTAGA.(SA.FAPi)2, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)2 and DOTAGA.Glu.(FAPi)2. were synthesized and quantitatively radiolabeled with 68Ga, 90Y, 177Lu and 225Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [225Ac]Ac-DOTAGA.Glu.(FAPi)2 in PBS. In vitro affinity studies resulted in subnanomolar IC50 values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [natLu]Lu-DOTAGA.Glu.(FAPi)2. In a first proof-of-principle patient study (medullary thyroid cancer), [177Lu]Lu-DOTAGA.Glu.(FAPi)2 was compared to [177Lu]Lu-DOTAGA.(SA.FAPi)2. High uptake and long tumor retention was observed in both cases, but [177Lu]Lu-DOTAGA.Glu.(FAPi)2 significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)2 showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [225Ac]Ac-DOTAGA.Glu.(FAPi)2 appear promising for translational application in patients.

Purpose Epilepsy is one of the most disabling neurological disorders, which affects all age groups and often results in severe consequences. Since misdiagnoses are common, many pediatric patients fail to receive the correct treatment. Recently, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging has been used for the evaluation of pediatric epilepsy. However, the epileptic focus is very difficult to be identified by visual assessment since it may present either hypo- or hyper-metabolic abnormality with unclear boundary. This study aimed to develop a novel symmetricity-driven deep learning framework of PET imaging for the identification of epileptic foci in pediatric patients with temporal lobe epilepsy (TLE). Methods We retrospectively included 201 pediatric patients with TLE and 24 age-matched controls who underwent 18F-FDG PET-CT studies. 18F-FDG PET images were quantitatively investigated using 386 symmetricity features, and a pair-of-cube (PoC)-based Siamese convolutional neural network (CNN) was proposed for precise localization of epileptic focus, and then metabolic abnormality level of the predicted focus was calculated automatically by asymmetric index (AI). Performances of the proposed framework were compared with visual assessment, statistical parametric mapping (SPM) software, and Jensen-Shannon divergence-based logistic regression (JS-LR) analysis. Results The proposed deep learning framework could detect the epileptic foci accurately with the dice coefficient of 0.51, which was significantly higher than that of SPM (0.24, P < 0.01) and significantly (or marginally) higher than that of visual assessment (0.31–0.44, P = 0.005–0.27). The area under the curve (AUC) of the PoC classification was higher than that of the JS-LR (0.93 vs. 0.72). The metabolic level detection accuracy of the proposed method was significantly higher than that of visual assessment blinded or unblinded to clinical information (90% vs. 56% or 68%, P < 0.01). Conclusion The proposed deep learning framework for 18F-FDG PET imaging could identify epileptic foci accurately and efficiently, which might be applied as a computer-assisted approach for the future diagnosis of epilepsy patients. Trial registration NCT04169581. Registered November 13, 2019 Public site: https://clinicaltrials.gov/ct2/show/NCT04169581

Purpose Standardized uptake value ratio (SUVr) used to quantify amyloid-β burden from amyloid-PET scans can be biased by variations in the tracer’s nonspecific (NS) binding caused by the presence of cerebrovascular disease (CeVD). In this work, we propose a novel amyloid-PET quantification approach that harnesses the intermodal image translation capability of convolutional networks to remove this undesirable source of variability. Methods Paired MR and PET images exhibiting very low specific uptake were selected from a Singaporean amyloid-PET study involving 172 participants with different severities of CeVD. Two convolutional neural networks (CNN), ScaleNet and HighRes3DNet, and one conditional generative adversarial network (cGAN) were trained to map structural MR to NS PET images. NS estimates generated for all subjects using the most promising network were then subtracted from SUVr images to determine specific amyloid load only (SAβL). Associations of SAβL with various cognitive and functional test scores were then computed and compared to results using conventional SUVr. Results Multimodal ScaleNet outperformed other networks in predicting the NS content in cortical gray matter with a mean relative error below 2%. Compared to SUVr, SAβL showed increased association with cognitive and functional test scores by up to 67%. Conclusion Removing the undesirable NS uptake from the amyloid load measurement is possible using deep learning and substantially improves its accuracy. This novel analysis approach opens a new window of opportunity for improved data modeling in Alzheimer’s disease and for other neurodegenerative diseases that utilize PET imaging.

Background: Alterations of hypothalamic–pituitary–adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. Objective: To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Study participants: Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. Methods: HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. Results: OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = −0.49, p = 0.009). Conclusion: The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

Over the last decades, there has been an increasing interest in dedicated preclinical imaging modalities for research in biomedicine. Especially in the case of positron emission tomography (PET), reconstructed images provide useful information of the morphology and function of an internal organ. PET data, stored as sinograms, involve the Radon transform of the image under investigation. The analytical approach to PET image reconstruction incorporates the derivative of the Hilbert transform of the sinogram. In this direction, in the present work we present a novel numerical algorithm for the inversion of the Radon transform based on Chebyshev polynomials of the first kind. By employing these polynomials, the computation of the derivative of the Hilbert transform of the sinogram is significantly simplified. Extending the mathematical setting of previous research based on Chebyshev polynomials, we are able to efficiently apply our new Chebyshev inversion scheme for the case of analytic preclinical PET image reconstruction. We evaluated our reconstruction algorithm on projection data from a small-animal image quality (IQ) simulated phantom study, in accordance with the NEMA NU 4-2008 standards protocol. In particular, we quantified our reconstructions via the image quality metrics of percentage standard deviation, recovery coefficient, and spill-over ratio. The projection data employed were acquired for three different Poisson noise levels: 100% (NL1), 50% (NL2), and 20% (NL3) of the total counts, respectively. In the uniform region of the IQ phantom, Chebyshev reconstructions were consistently improved over filtered backprojection (FBP), in terms of percentage standard deviation (up to 29% lower, depending on the noise level). For all rods, we measured the contrast-to-noise-ratio, indicating an improvement of up to 68% depending on the noise level. In order to compare our reconstruction method with FBP, at equal noise levels, plots of recovery coefficient and spill-over ratio as functions of the percentage standard deviation were generated, after smoothing the NL3 reconstructions with three different Gaussian filters. When post-smoothing was applied, Chebyshev demonstrated recovery coefficient values up to 14% and 42% higher, for rods 1–3 mm and 4–5 mm, respectively, compared to FBP, depending on the smoothing sigma values. Our results indicate that our Chebyshev-based analytic reconstruction method may provide PET reconstructions that are comparable to FBP, thus yielding a good alternative to standard analytic preclinical PET reconstruction methods.

Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored nuclear techniques including positron emission tomography (PET) to evaluate the delivery of UC-MSC-EVs in vivo. In this study, human UC-MSC-EVs were first successfully tagged with I-124 to permit PET determination. Intravenous (I.V.) and intra-arterial (I.A.) administration routes of [124I]I-UC-MSC-EVs were compared and evaluated by in vivo PET-CT imaging and ex vivo biodistribution in a non-diabetic Lewis (LEW) rat model. For I.A. administration, [124I]I-UC-MSC-EVs were directly infused into the pancreatic parenchyma via the celiac artery. PET imaging revealed that the predominant uptake occurred in the liver for both injection routes, and further imaging characterized clearance patterns of [124I]I-UC-MSC-EVs. For biodistribution, the uptake (%ID/gram) in the spleen was significantly higher for I.V. administration compared to I.A. administration (1.95 ± 0.03 and 0.43 ± 0.07, respectively). Importantly, the pancreas displayed similar uptake levels between the two modalities (0.20 ± 0.06 for I.V. and 0.24 ± 0.03 for I.A.). Therefore, our initial data revealed that both routes had similar delivery efficiency for [124I]I-UC-MSC-EVs except in the spleen and liver, considering that higher spleen uptake could enhance immunomodulatory application of UC-MSC-EVs. These findings could guide the development of safe and efficacious delivery strategies for UC-MSC-EVs in diabetes therapies, in which a minimally invasive I.V. approach would serve as a better delivery strategy. Further confirmation studies are ongoing.

Antibodies are attractive as radioligands due to their outstanding specificity and high affinity, but their inability to cross the blood–brain barrier (BBB) limits their use for CNS targets. To enhance brain distribution, amyloid-β (Aβ) antibodies were fused to a transferrin receptor (TfR) antibody fragment, enabling receptor mediated transport across the BBB. The aim of this study was to label these bispecific antibodies with fluorine-18 and use them for Aβ PET imaging. Bispecific antibody ligands RmAb158-scFv8D3 and Tribody A2, both targeting Aβ and TfR, were functionalized with trans-cyclooctene (TCO) groups and conjugated with 18F-labeled tetrazines through an inverse electron demand Diels–Alder reaction performed at ambient temperature. 18F-labeling did not affect antibody binding in vitro, and initial brain uptake was high. Conjugates with the first tetrazine variant ([18F]T1) displayed high uptake in bone, indicating extensive defluorination, a problem that was resolved with the second and third tetrazine variants ([18F]T2 and [18F]T3). Although the antibody ligands’ half-life in blood was too long to optimally match the physical half-life of fluorine-18 (t1/2 = 110 min), [18F]T3-Tribody A2 PET seemed to discriminate transgenic mice (tg-ArcSwe) with Aβ deposits from wild-type mice 12 h after injection. This study demonstrates that 18F-labeling of bispecific, brain penetrating antibodies is feasible and, with further optimization, could be used for CNS PET imaging.

Voxel-based morphometry (VBM) analysis of nuclear Magnetic Resonance Imaging (MRI) data allows the identification of medial temporal lobe (MTL) atrophy and is widely used to assist the diagnosis of Alzheimer’s disease (AD). However, its reliability in the clinical environment has not yet been confirmed. To determine the credibility of VBM, amyloid positron emission tomography (PET) and VBM studies were compared retrospectively. Patients who underwent Pittsburgh Compound B (PiB) PET were retrospectively recruited. Ninety-seven patients were found to be amyloid negative and 116 were amyloid positive. MTL atrophy in the PiB positive group, as quantified by thin sliced 3D MRI and VBM software, was significantly more severe (p =0.0039) than in the PiB negative group. However, data histogram showed a vast overlap between the two groups. The area under the ROC curve (AUC) was 0.646. MMSE scores of patients in the amyloid negative and positive groups were also significantly different (p = 0.0028), and the AUC was 0.672. Thus, MTL atrophy could not reliably differentiate between amyloid positive and negative patients in a clinical setting, possibly due to the wide array of dementia-type diseases that exist other than AD.

Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, a single domain shark antibody VNAR fragment (TXB2) with similar affinity to murine and human TfR1 was used to shuttle protein cargo into the brain. TXB2 was fused to a human IgG1 Fc domain (hFc) or to the amyloid-β (Aβ) antibody bapineuzumab (Bapi). TXB2-hFc displayed 20-fold higher brain concentrations compared with a control VNAR-hFc at 18 hours post-injection in wt mice. At the same time point, brain concentrations of Bapi-TXB2 was threefold higher than Bapi. In transgenic mice overexpressing human Aβ, the brain-to-blood concentration ratio increased with time due to interaction with intracerebral Aβ deposits. The relatively stable threefold difference between Bapi-TXB2 and Bapi was observed for up to 6 days after injection. PET imaging and ex vivo autoradiography revealed more parenchymal distribution of Bapi-TXB2 compared with Bapi. In conclusion, the TXB2 VNAR shuttle markedly increased brain uptake of protein cargo and increased brain concentrations of the Aβ binding antibody Bapi.

[EN] Molecular imaging systems, such as positron emission tomography (PET), use detectors providing energy and a 3-D interaction position of a gamma ray within a scintillation block. Monolithic crystals are becoming an alternative to crystal arrays in PET. However, calibration processes are required to correct for nonuniformities, mainly produced by the truncation of the scintillation light distribution at the edges. We propose a calibration method based on the Voronoi diagrams. We have used $50 \times 50 \times 15$ mm(3) LYSO blocks coupled to a $12\times 12$ SiPMs array. We have first studied two different interpolation algorithms: 1) weighted average method (WAM) and 2) natural neighbor (NN). We have compared them with an existing calibration based on 1-D monomials. Here, the crystal was laterally black painted and a retroreflector (RR) layer added to the entrance face. The NN exhibited the best results in terms of XY impact position, depth of Interaction, and energy, allowing us to calibrate the whole scintillation volume. Later, the NN interpolation has been tested against different crystal surface treatments, allowing always to correct edge effects. Best energy resolutions were observed when using the reflective layers (12%-14%). However, better linearity was observed with the treatments using black paint. In particular, we obtained the best overall performance when lateral black paint is combined with the RR., This work was supported in part by the European Research Council through the European Union's Horizon 2020 Research and Innovation Program under Grant 695536, and in part by the Spanish Ministerio de Economia, Industria y Competitividad under Grant TEC2016-79884-C2-1-R.

Background Activated microglia play a complex role in neuroinflammation associated with acute ischaemic stroke. As a potential target for anti-inflammatory therapy, it is crucial to understand the association between intensity, extent and the clinical outcome of a stroke. The 18-kDa translocator protein is a marker of cerebral microglial activation and of macrophage infiltration after damage to the brain. It can be imaged by positron emission tomography. Therefore, the recently developed radiopharmaceutical [18F]-GE180 was used in patients after a mild to moderate stroke and compared with [11C]-(R)-PK11195, which has already been established in research but cannot be used in routine clinical settings because of its very short half-life. Objectives Objectives for phase 1 were to evaluate the tolerability of positron emission tomography scanning, to assess the technical feasibility of imaging the 18-kDa translocator protein using [18F]-GE180 as radiopharmaceutical, to compare [18F]-GE180 with [11C]-(R)-PK11195 as reference. Objectives for phase 2 were examining the relation of positron emission tomography imaging with clinical outcome, magnetic resonance imaging and systemic inflammation. However, the study was ended after phase 1 because of the results obtained in that phase and did not enter phase 2. Methods Ten participants (aged 24–89 years, median 68 years) (eight male and two female) with a history of recent ischaemic stroke of mild to moderate severity (modified Rankin scale score of 2–3) in the middle cerebral artery territory were scanned 18 to 63 days (median 34.5 days) after the stroke by magnetic resonance imaging (Philips 1.5 T; Philips, Amsterdam, the Netherlands), [18F]-GE180 (200 MBq, 30-minute dynamic scan) and [11C]-(R)-PK11195 (740 MBq, 60-minute dynamic scan) positron emission tomography (Siemens HRRT; Siemens, Munich, Germany). The two positron emission tomography scans were performed on 2 separate days (mean 3.4 days apart). Five patients were randomised to receive the [18F]-GE180 scan at the first session and five patients were randomised to receive it at the second session. Participants were genotyped for the rs6971 18-kDa translocator protein polymorphism, which is known to affect binding of [18F]-GE180 but not of [11C]-(R)-PK11195. All positron emission tomography and magnetic resonance data sets were co-registered with T1-weighted magnetic resonance image scans. Binding of [18F]-GE180 was compared with [11C]-(R)-PK11195 for the infarct and contralateral reference regions. Spearman’s rank-order correlation was used to compare tracers, t-tests to compare patient subgroups. Results Tolerability of scans was rated as 4.36 (range 4–5) out of a maximum of 5 by participants, and there were no serious adverse events. There was a close correlation between [18F]-GE180 and [11C]-(R)-PK11195 (r = 0.79 to 0.84). The 18-kDa translocator protein polymorphism had a significant impact on the uptake of [18F]-GE180, which was very low in normal cortex. Ischaemic lesions with contrast enhancement on magnetic resonance as an indicator of blood–brain barrier damage showed a significantly higher uptake of [18F]-GE180 than the lesions without enhancement, even in low-affinity binders. Conclusions [18F]-GE180 was safe and well tolerated. However, strong dependency of uptake on blood–brain barrier damage and a genetic 18-kDa translocator protein polymorphism, as well as a high contribution of vascular signal to the uptake and evidence of non-specific binding in ischaemic lesions with blood–brain barrier damage, limits the clinical applicability of [18F]-GE180 as a diagnostic marker of neuroinflammation. Limitations As the study was ended after phase 1, this was only a small pilot trial. Further studies are warranted to fully understand the influence of blood–brain barrier damage on positron emission tomography microglia imaging. Trial registration Registered as a clinical trial with EudraCT 2014-000591-26. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 1. See the NIHR Journals Library website for further information. It was also supported by GE Healthcare (Chicago, IL, USA) by free production and delivery of [18F]-GE180 and by supply of regulatory documents (Investigational Medical Product Dossier, Investigator’s Brochure). There was partial support by the European Commission (INMiND, grant #278850) and the NIHR Sheffield Biomedical Research Centre.

AimUnderstanding neuroinflammation after acute ischemic stroke is a crucial step on the way to an individualized post-stroke treatment. Microglia activation, an essential part of neuroinflammation, can be assessed using [18F]GE-180 18 kDa translocator protein positron emission tomography (TSPO-PET). However, the commonly used 60–90 min post-injection (p.i.) time window was not yet proven to be suitable for post-stroke neuroinflammation assessment. In this study, we compare semi-quantitative estimates derived from late time frames to quantitative estimates calculated using a full 0–90 min dynamic scan in a mouse photothrombotic stroke (PT) model.Materials and MethodsSix mice after PT and six sham mice were included in the study. For a half of the mice, we acquired four serial 0–90 min scans per mouse (analysis cohort) and calculated standardized uptake value ratios (SUVRs; cerebellar reference) for the PT volume of interest (VOI) in five late 10 min time frames as well as distribution volume ratios (DVRs) for the same VOI. We compared late static 10 min SUVRs and the 60–90 min time frame of the analysis cohort to the corresponding DVRs by linear fitting. The other half of the animals received a static 60–90 min scan and was used as a validation cohort. We extrapolated DVRs by using the static 60–90 min p.i. time window, which were compared to the DVRs of the analysis cohort.ResultsWe found high linear correlations between SUVRs and DVRs in the analysis cohort for all studied 10 min time frames, while the fits of the 60–70, 70–80, and 80–90 min p.i. time frames were the ones closest to the line of identity. For the 60–90 min time window, we observed an excellent linear correlation between SUVR and DVR regardless of the phenotype (PT vs. sham). The extrapolated DVRs of the validation cohort were not significantly different from the DVRs of the analysis group.ConclusionSimplified quantification by a reference tissue ratio of the late 60–90 min p.i. [18F]GE-180 PET image can replace full quantification of a dynamic scan for assessment of microglial activation in the mouse PT model.

When treating patients with a disorder of consciousness (DOC), it is essential to obtain an accurate diagnosis as soon as possible to generate individualized treatment programs. However, accurately diagnosing patients with DOCs is challenging and prone to errors when differentiating patients in a Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) from those in a Minimally Conscious State (MCS). Upwards of ~40% of patients with a DOC can be misdiagnosed when specifically designed behavioral scales are not employed or improperly administered. To improve diagnostic accuracy for these patients, several important neuroimaging and electrophysiological technologies have been proposed. These include Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), Electroencephalography (EEG), and Transcranial Magnetic Stimulation (TMS). Here, we review the different ways in which these techniques can improve diagnostic differentiation between VS/UWS and MCS patients. We do so by referring to studies that were conducted within the last 10 years, which were extracted from the PubMed database. In total, 55 studies met our criteria (clinical diagnoses of VS/UWS from MCS as made by PET, fMRI, EEG and TMS- EEG tools) and were included in this review. By summarizing the promising results achieved in understanding and diagnosing these conditions, we aim to emphasize the need for more such tools to be incorporated in standard clinical practice, as well as the importance of data sharing to incentivize the community to meet these goals.

Peripheral arterial disease (PAD) is an atherosclerotic disorder of non-coronary arteries that is associated with vascular stenosis and/or occlusion. PAD affecting the lower extremities is characterized by a variety of health-related consequences, including lifestyle-limiting intermittent claudication, ulceration of the limbs and/or feet, increased risk for lower extremity amputation, and increased mortality. The diagnosis of lower extremity PAD is typically established by using non-invasive tests such as the ankle-brachial index, toe-brachial index, duplex ultrasound, and/or angiography imaging studies. While these common diagnostic tools provide hemodynamic and anatomical vascular assessments, the potential for non-invasive physiological assessment of the lower extremities has more recently emerged through the use of magnetic resonance- and nuclear medicine-based approaches, which can provide insight into the functional consequences of PAD-related limb ischemia. This perspectives article specifically highlights and discusses the emerging applications of clinical nuclear medicine techniques for molecular imaging investigations in the setting of lower extremity PAD.

Purpose Positron emission tomography (PET) with the first and only tau targeting radiotracer of F-18-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform F-18-flortaucipir PET imaging. Method A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for F-18-flortaucipir PET imaging in Alzheimer's disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. Conclusion This international consensus and practice guideline will help to promote the standardized use of F-18-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.

Melodic Intonation Therapy (MIT) is one of the most well-known therapies for the rehabilitation of speech in patients with non-fluent aphasia and which is thought to promote right-hemisphere involvement in language processing. This review focuses on the study of language lateralization and/or neuroplastic reorganization with neuroimaging and/or neurophysiological techniques in non-fluent aphasic patients post-stroke during or after MIT. A systematic search was carried out according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) in databases (PubMed, Scopus, EMBASE, Dialnet, Web of Science, Cochrane) with the keywords melodic intonation therapy, neuroimaging, functional magnetic resonance, and positron emission tomography and the boolean operators AND and OR. Articles including patients of all ages and either sex with any type of aphasia post-stroke and in any language, which studied language lateralization and/or neuroplastic reorganization after or during MIT were included. Articles which did not achieve the objectives, revisions and conferences were excluded. Different results were obtained from the 16 studies included in the review: predominantly greater activation of the right hemisphere but also of the left hemisphere or both. MIT is an effective therapy to rehabilitate non-fluent aphasic patients post-stroke. It involves different neurobiological mechanisms and depends on multiple individual factors. Studies with larger samples are necessary. Open access funding provided by University of Málaga and PAIDI Group CTS 159.

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with 68Ga (t1/2 = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720—an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 (PEGn: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 high cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [68Ga]Ga-DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 in SSTR2high prostate cancer xenografts than in the SSTR2low xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.

Since NGR-tripeptides (asparagine-glycine-arginine) selectively target neoangiogenesis-associated Aminopeptidase N (APN/CD13) on cancer cells, we aimed to evaluate the in vivo tumour targeting capability of radiolabelled, NGR-containing, ANP/CD13-selective [213Bi]Bi-DOTAGA-cKNGRE in CD13pos. HT1080 fibrosarcoma-bearing severe combined immunodeficient CB17 mice. 10 ± 1 days after cancer cell inoculation, positron emission tomography (PET) was performed applying [68Ga]Ga-DOTAGA-cKNGRE for tumour verification. On the 7th, 8th, 10th and 12th days the treated group of tumourous mice were intraperitoneally administered with 4.68 ± 0.10 MBq [213Bi]Bi-DOTAGA-cKNGRE, while the untreated tumour-bearing animals received 150 μL saline solution. In addition to body weight (BW) and tumour volume measurements, ex vivo biodistribution studies were conducted 30 and 90 min postinjection (pi.). The following quantitative standardised uptake values (SUV) confirmed the detectability of the HT1080 tumours: SUVmean and SUVmax: 0.37 ± 0.09 and 0.86 ± 0.14, respectively. Although no significant difference (p ≤ 0.05) was encountered between the BW of the treated and untreated mice, their tumour volumes measured on the 9th, 10th and 12th days differed significantly (p ≤ 0.01). Relatively higher [213Bi]Bi-DOTAGA-cKNGRE accumulation of the HT1080 neoplasms (%ID/g: 0.80 ± 0.16) compared with the other organs at 90 min time point yields better tumour-to-background ratios. Therefore, the therapeutic application of APN/CD13-affine [213Bi]Bi-DOTAGA- cKNGRE seems to be promising in receptor-positive fibrosarcoma treatment.

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions.

Purpose Amygdalar metabolic activity was shown to independently predict cardiovascular outcomes. However, little is known about age- and sex-dependent variability in neuronal stress responses among individuals free of cardiac disease. This study sought to assess age- and sex-specific differences of resting amygdalar metabolic activity in the absence of clinical cardiovascular disease. Methods Amygdalar metabolic activity was assessed in 563 patients who underwent multimodality imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography and echocardiography for the evaluation of cardiac function. Results After exclusion of 294 patients with structural or functional cardiovascular pathologies, 269 patients (128 women) remained in the final population. 18F-FDG amygdalar activity significantly decreased with age in men (r = − 0.278, P = 0.001), but not in women (r = 0.002, P = 0.983). Similarly, dichotomous analysis confirmed a lower amygdalar activity in men ≥ 50 years as compared to those

Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters.Methods:18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke’s Cognitive Examination–Revised, and Frontal Assessment Battery, Unified Parkinson’s Disease Rating Scale Motor Score, and PSP Rating Scale.Results:18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP.Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.

Tumor hypoxia induces angiogenesis, which is required for tumor cell survival. The aminopeptidase N receptor (APN/CD13) is an excellent marker of angiogenesis since it is overexpressed in angiogenic blood vessels and in tumor cells. Asparagine-glycine-arginine (NGR) peptide analogs bind selectively to the APN/CD13 recepto, therefore, they are important vector molecules in the development of a PET radiotracer which is capable of detecting APN-rich tumors. To investigate the effect of glycosylation and pegylation on in-vivo efficacy of an NGR-based radiotracer, two 68Ga-labeled radioglycopeptides were synthesized. A lactosamine derivative was applied to glycosylation of the NGR derivative and PEG4 moiety was used for pegylation. The receptor targeting potential and biodistribution of the radiopeptides were evaluated with in vivo PET imaging studies and ex vivo tissue distribution studies using B16-F10 melanoma tumor-bearing mice. According to these studies, all synthesized radiopeptides were capable of detecting APN expression in B16-F10 melanoma tumor. In addition, lower hepatic uptake, higher tumor-to background (T/M) ratio and prolonged circulation time were observed for the novel [68Ga]-10 radiotracer due to pegylation and glycosylation, resulting in more contrasting PET imaging. These in vivo PET imaging results correlated well with the ex vivo tissue distribution data.

BackgroundImaging diagnosis of inflammation has been challenging for many years. Inflammation imaging agents commonly used in nuclear medicine, such as [67Ga]Ga-citrate and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) showed some limitations. The identification of a radiotracer with high specificity and low radiation dose is clinically important. With the commercialization of68Ge/68Ga generators and the high68Ga cyclotron production capacity, the study of68Ga-based tracer for inflammation has increased and shown good potential. In the present work, we report the synthesis of 4HMSA, a new acyclic chelator, and its first investigation for68Ga complexation and as a new positron emission tomography (PET) imaging agent of inflammation in comparison to [68Ga]Ga-citrate.ResultsThe present experimental studies have shown that the novel [68Ga]Ga-4HMSA is stable allowing imaging of inflammation in a preclinical model of adjuvant- and pathogen-based inflammation involving intraplantar injection of complete Freund’s adjuvant (CFA). We also found that [68Ga]Ga-4HMSA displayed similar uptakes in the inflamed paw than [68Ga]Ga-citrate, which are superior compared to those of contralateral (non-injected) paws at days 1–3 from PET imaging. [68Ga]Ga-citrate accumulated in the upper body of the animal such as the liver, lungs and the heart, whereas the [68Ga]Ga-4HMSA revealed low uptakes in the majority of the organs and was cleared relatively rapidly from blood circulation through the kidneys and bladder.ConclusionThe results highlight the potential of [68Ga]Ga-4HMSA as an interesting alternative to [68Ga]Ga-citrate for inflammation imaging by PET. The new PET tracer also offers additional advantages than [68Ga]Ga-citrate in term of dosimetry and lower overall background activity.

Purpose We aimed to investigate the predictive models based on O-[2-(18F)fluoroethyl]-l-tyrosine positron emission tomography/computed tomography (18F-FET PET/CT) radiomics features for the isocitrate dehydrogenase (IDH) genotype identification in adult gliomas. Methods Fifty-eight consecutive pathologically confirmed adult glioma patients with pretreatment 18F-FET PET/CT were retrospectively enrolled. One hundred and five radiomics features were extracted for analysis in each modality. Three independent radiomics models (PET-Rad Model, CT-Rad Model and PET/CT-Rad Model) predicting IDH mutation status were generated using the least absolute shrinkage and selection operator (LASSO) regression analysis based on machine learning algorithms. All-subsets regression and cross validation were applied for the filter and calibration of the predictive radiomics models. Besides, semi-quantitative parameters including maximum, peak and mean tumor to background ratio (TBRmax, TBRpeak, TBRmean), standard deviation of glioma lesion standardized uptake value (SUVSD), metabolic tumor volume (MTV) and total lesion tracer uptake (TLU) were obtained and filtered for the simple model construction with clinical feature of brain midline involvement status. The area under the receiver operating characteristic curve (AUC) was applied for the evaluation of the predictive models. Results The AUC of the simple predictive model consists of semi-quantitative parameter SUVSD and dichotomized brain midline involvement status was 0.786 (95% CI 0.659-0.883). The AUC of PET-Rad Model building with three 18F-FET PET radiomics parameters was 0.812 (95% CI 0.688-0.902). The AUC of CT-Rad Model building with three co-registered CT radiomics parameters was 0.883 (95% CI 0.771-0.952). While the AUC of the combined 18F-FET PET/CT-Rad Model building with three CT and one PET radiomics features was 0.912 (95% CI 0.808-0.970). DeLong test results indicated the PET/CT-Rad Model outperformed the PET-Rad Model (p = 0.048) and simple predictive model (p = 0.034). Further combination of the PET/CT-Rad Model with the clinical feature of dichotomized tumor location status could slightly enhance the AUC to 0.917 (95% CI 0.814-0.973). Conclusion The predictive model combining 18F-FET PET and integrated CT radiomics features could significantly enhance and well balance the non-invasive IDH genotype prediction in untreated gliomas, which is important in clinical decision making for personalized treatment.

Brain metastases affect more breast cancer patients than ever before due to increased overall patient survival with improved molecularly targeted treatments. Approximately 25–34% of breast cancer patients develop brain metastases in their lifetime. Due to the blood–brain barrier (BBB), the standard treatment for breast cancer brain metastases (BCBM) is surgery, stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT). At the cost of cognitive side effects, WBRT has proven efficacy in treating brain metastases when used with local therapies such as SRS and surgery. This review investigated the potential use of glial activation positron emission tomography (PET) imaging for radiation treatment of BCBM. In order to put these studies into context, we provided background on current radiation treatment approaches for BCBM, our current understanding of the brain microenvironment, its interaction with the peripheral immune system, and alterations in the brain microenvironment by BCBM and radiation. We summarized preclinical literature on the interactions between glial activation and cognition and clinical studies using translocator protein (TSPO) PET to image glial activation in the context of neurological diseases. TSPO-PET is not employed clinically in assessing and guiding cancer therapies. However, it has gained traction in preclinical studies where glial activation was investigated from primary brain cancer, metastases and radiation treatments. Novel glial activation PET imaging and its applications in preclinical studies using breast cancer models and glial immunohistochemistry are highlighted. Lastly, we discuss the potential clinical application of glial activation imaging to improve the therapeutic ratio of radiation treatments for BCBM.

Simple Summary Visceral involvement in prostate cancer (PCa) represents a negative prognostic factor. Liver metastases typically occur in systemic, late-stage, castration-resistant prostate cancer (CRPC). The diagnostic performance of [68Ga]Ga-PSMA-11-PET for visceral metastases of CRPC patients has never been systematically assessed. Our aim was to evaluate the diagnostic performance of PSMA-PET compared to conventional imaging, i.e., CT or MRI, or liver biopsy in the detection of liver metastases in CRPC patients. The secondary aim was to assess the ability of radiomics to predict the presence of liver metastases. Regarding liver metastases assessment in CRPC patients, [68Ga]-PSMA-11-PET demonstrated moderate sensitivity while high specificity, positive predictive value, and reproducibility compared to conventional imaging and liver biopsy. However, nuclear medicine physicians should carefully assess the liver parenchyma on PET images, especially in patients at higher risk for liver metastases and with high PSA values. Moreover, radiomic features may aid in recognizing higher-risk patients to develop them. Background: To evaluate the diagnostic performance of PSMA-PET compared to conventional imaging/liver biopsy in the detection of liver metastases in CRPC patients. Moreover, we evaluated a PSMA-PET/CT-based radiomic model able to identify liver metastases. Methods: Multicenter retrospective study enrolling patients with the following inclusion criteria: (a) proven CRPC patients, (b) PSMA-PET and conventional imaging/liver biopsy performed in a 6 months timeframe, (c) no therapy changes between PSMA-PET and conventional imaging/liver biopsy. PSMA-PET sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for liver metastases were calculated. After the extraction of radiomic features, a prediction model for liver metastases identification was developed. Results: Sixty CRPC patients were enrolled. Within 6 months before or after PSMA-PET, conventional imaging and liver biopsy identified 24/60 (40%) patients with liver metastases. PSMA-PET sensitivity, specificity, PPV, NPV, and accuracy for liver metastases were 0.58, 0.92, 0.82, 0.77, and 0.78, respectively. Either number of liver metastases and the maximum lesion diameter were significantly associated with the presence of a positive PSMA-PET (p < 0.05). On multivariate regression analysis, the radiomic feature-based model combining sphericity, and the moment of inverse difference (Idm), had an AUC of 0.807 (95% CI:0.686-0.920). Conclusion: For liver metastases assessment, [68Ga]Ga-PSMA-11-PET demonstrated moderate sensitivity while high specificity, PPV, and inter-reader agreement compared to conventional imaging/liver biopsy in CRPC patients.

Cerebral blood flow (CBF) / cerebral blood volume (CBV) ratio derived by [15O] H2O/ CO2 and CO positron emission tomography (PET) examination has been used as an index for cerebral perfusion pressure (CPP). CBF/CBV was demonstrated to be related mean arterial pressure (MAP) in baboons. However, this formula has not been confirmed to be proportionate to CPP. We have developed a new index for CPP using the Poiseuille equation based on a simple model. Our model suggests that CBF/CBV2 is proportionate to CPP and that it is mathematically a more accurate index than CBF/CBV. This new index needs experimental validation in the future.

Delivery of most drugs into the central nervous system (CNS) is restricted by the blood–brain barrier (BBB), which remains a significant bottleneck for development of novel CNS-targeted therapeutics or molecular tracers for neuroimaging. Consistent failure to reliably predict drug efficiency based on single measures for the rate or extent of brain penetration has led to the emergence of a more holistic framework that integrates data from various in vivo, in situ and in vitro assays to obtain a comprehensive description of drug delivery to and distribution within the brain. Coupled with ongoing development of suitable in vitro BBB models, this integrated approach promises to reduce the incidence of costly late-stage failures in CNS drug development, and could help to overcome some of the technical, economic and ethical issues associated with in vivo studies in animal models. Here, we provide an overview of BBB structure and function in vivo, and a summary of the pharmacokinetic parameters that can be used to determine and predict the rate and extent of drug penetration into the brain. We also review different in vitro models with regard to their inherent shortcomings and potential usefulness for development of fast-acting drugs or neurotracers labeled with short-lived radionuclides. In this regard, a special focus has been set on those systems that are sufficiently well established to be used in laboratories without significant bioengineering expertise.

An early detection and intervention for dementia represent tremendous unmet clinical needs and priorities in society. A shared feature of neurodegenerative diseases causing dementia is the abnormal accumulation and spreading of pathological protein aggregates, which affect the selective vulnerable circuit in a disease-specific pattern. The advancement in positron emission tomography (PET) biomarkers has accelerated the understanding of the disease mechanism and development of therapeutics for Alzheimer’s disease and Parkinson’s disease. The clinical utility of amyloid-β PET and the clinical validity of tau PET as diagnostic biomarker for Alzheimer’s disease continuum have been demonstrated. The inclusion of biomarkers in the diagnostic criteria has introduced a paradigm shift that facilitated the early and differential disease diagnosis and impacted on the clinical management. Application of disease-modifying therapy likely requires screening of patients with molecular evidence of pathological accumulation and monitoring of treatment effect assisted with biomarkers. There is currently still a gap in specific 4-repeat tau imaging probes for 4-repeat tauopathies and α-synuclein imaging probes for Parkinson’s disease and dementia with Lewy body. In this review, we focused on recent development in molecular imaging biomarkers for assisting the early diagnosis of proteinopathies (i.e., amyloid-β, tau, and α-synuclein) in dementia and discussed future perspectives.

BackgroundAccurate staging of early breast cancer (BC) patients is essential for tailored treatment. Currently, the preferred imaging modality for staging is positron emission tomography with [18F]Fluorodeoxyglucose (FDG PET) combined with a diagnostic computed tomography (CT) scan of the thorax/abdomen. However, FDG PET might be insufficient for detection of malignant lesions in grade 1–2, estrogen receptor positive (ER+) BC, due to its low metabolic activity. The main aim of this study was to retrospectively investigate the diagnostic accuracy of FDG PET in this patient population.Methods74 patients diagnosed with grade 1–2, ER + clinical stage IIB/III or locoregional recurrent BC were included. Suspect tumor lesions detected on conventional imaging (mammography, ultrasound, magnetic resonance imaging, diagnostic CT, bone scintigraphy) and FDG PET were confirmed with pathology or follow-up. FDG PET-positive lesions were (semi)quantified with standardized uptake values (SUV) and total lesion glycolysis (TLG), and these FDG PET parameters were correlated with pathological features such as histological subtype, grade, ER, PR and HER2 expression and mitotic activity index.ResultsPre-operative imaging identified 155 lesions that were pathologically verified. Based on pathology, 115/155 (74.2%) lesions identified on FDG PET were classified as true positive, i.e. malignant (in 67 patients) and 17/155 (10.8%) lesions as false positive, i.e. benign (in 9 patients); 7/155 (4.5%) as false negative (in 7 patients) and 16/155 (10.3%) as true negative (in 14 patients). FDG PET incorrectly staged 16/70 (22.9%) patients: 3/70 (4.3%) were downstaged whereas 13/70 (18.6%) were upstaged. SUV did not help to discriminate between true- and false positive lesions (median SUVmax 4.23, IQR: 2.54–6.37 vs. 3.07, IQR: 2.14–5.58, P = 0.44 respectively). For true positive lesions, FDG uptake correlated with histological subtype, showing higher uptake in ductal carcinoma compared to lobular carcinoma (P

Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

18F-Labeled blood pool agents (BPAs) have attracted great attention for identifying bleeding sites. However, many BPAs are not sufficiently evaluated partially due to the limitations of labeling methods. In our previous work, we noticed that 18F-PEG1-vinyl sulfone (18F-VS) could efficiently label red blood cells (RBCs) ex vivo and in situ. However, its application as BPA is not fully evaluated. In this study, we systematically explored the feasibility of using 18F-VS-labeled RBCs as a positron emission tomography (PET) BPA for intra-abdominal bleeding diagnosis. In brief, we first optimized the labeling conditions, which lead to an 80% labeling yield of RBCs after incubating with 18F-VS in phosphate-buffered saline (PBS) at 37°C for 20 min. 18F-VS-labeled RBCs were found to be stable in vitro, which could simplify its transportation/storage for in vivo applications. In normal rat PET study, the cardiovascular system could be clearly imaged up to 5 h post injection (p.i.). An intra-abdominal hemorrhage rat model demonstrated that the 18F-VS-labeled RBCs clearly showed the dynamic changes of extravascular radioactivity due to intra-abdominal hemorrhage. Validation in the model of gastrointestinal bleeding clearly demonstrated the great potential of using 18F-VS-labeled RBCs as a BPA, which could be further evaluated in future studies.

This review addresses the challenges of primary central nervous system (CNS) lymphoma diagnosis, assessment of treatment response, and detection of recurrence. Primary CNS lymphoma is a rare form of extra-nodal non-Hodgkin lymphoma that can involve brain, spinal cord, leptomeninges, and eyes. Primary CNS lymphoma lesions are most commonly confined to the white matter or deep cerebral structures such as basal ganglia and deep periventricular regions. Contrast-enhanced magnetic resonance imaging (MRI) is the standard diagnostic modality employed by neuro-oncologists. MRI often shows common morphological features such as a single or multiple uniformly well-enhancing lesions without necrosis but with moderate surrounding edema. Other brain tumors or inflammatory processes can show similar radiological patterns, making differential diagnosis difficult. [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) has selected utility in cerebral lymphoma, especially in diagnosis. Primary CNS lymphoma can sometimes present with atypical findings on MRI and FDG PET, such as disseminated disease, non-enhancing or ring-like enhancing lesions. The complementary strengths of PET and MRI have led to the development of combined PET-MR systems, which in some cases may improve lesion characterization and detection. By highlighting active developments in this field, including advanced MRI sequences, novel radiotracers, and potential imaging biomarkers, we aim to spur interest in sophisticated imaging approaches.

Compartmental analysis is the mathematical framework for the modelling of tracer kinetics in dynamical Positron Emission Tomography. This paper provides a review of how compartmental models are constructed and numerically optimized. Specific focus is given on the identifiability and sensitivity issues and on the impact of complex physiological conditions on the mathematical properties of the models.

The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [18F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [18F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use.

Due to its high sensitivity and specificity for tumor detection, positron emission tomography (PET) has become a standard and widely used molecular imaging technique. Given the popularity of PET, both clinically and preclinically, its use has been extended to study plants. However, only a limited number of research groups worldwide report PET-based studies, while we believe that this technique has much more potential and could contribute extensively to plant science. The limited application of PET may be related to the complexity of putting together methodological developments from multiple disciplines, such as radio-pharmacology, physics, mathematics and engineering, which may form an obstacle for some research groups. By means of this manuscript, we want to encourage researchers to study plants using PET. The main goal is to provide a clear description on how to design and execute PET scans, process the resulting data and fully explore its potential by quantification via compartmental modeling. The different steps that need to be taken will be discussed as well as the related challenges. Hereby, the main focus will be on, although not limited to, tracing 11CO2 to study plant carbon dynamics.

In this paper, an FPGA-based plain delay line time-to-digital converters (TDC) is presented, together with a theoretical model on its timing properties. The TDC features an automated calibration system implemented in the on-chip processor of an SoC-FPGA, uses a low amount of FPGA resources and is therefore suitable for applications requiring a high number of channels, such as time-of-flight positron emission tomography (PET). We first investigated the importance of calibration and validated the theoretical model on the TDC timing properties. Finally, the device has been embodied into a two channel PET acquisition system and tested. We found the calibration essential to obtain a good time resolution (38-ps FWHM in comparison with a 78-ps FWHM obtained with the uncalibrated device). The model we developed is able to predict the TDC timing properties. They are shown to be related to the fundamental parameters of the used FPGA technology. In particular, the best achievable time resolution of this specific architecture (plain tapped delay line on FPGA) is set to about 30 ps by the sum of the setup and hold times of the registers in the FPGA. The timing resolution of the two-channel setup is about 118 ps.